title: HPLC method validation for the quantification of lomustine to study pharmacokinetics of thermosensitive liposome-encapsulated lomustine containing iohexol for CT imaging in C6 glioma rats.
abstract: To study the pharmacokinetics of the novel lomustine liposome, a specific, simple, and reliable high-performance liquid chromatography with ultraviolet detection (HPLC/UV) method for quantification of lomustine in rat plasma was established and validated. The calibration curve was linear over the concentration range of 0.05-5 μg/mL with the linearity (r (2)) being ≥0.9994. The intra- and inter-day precision was less than 5.87 and 10.47%, respectively, and the accuracy was within ±7.95%. The validated method has been successfully applied to a pharmacokinetic study of thermosensitive liposome-encapsulated lomustine containing iohexol and lomustine solution after intravenous administration to C6 glioma rats. Population pharmacokinetic (PPK) analysis was performed using NONMEM program for the plasma concentration versus time data. A one-compartment model with first-order elimination was established and proved to be the best description of the lomustine profile. Bootstrap analysis (n = 1,000) was executed to evaluate the stability and robustness of the model. The pharmacokinetic parameters of lomustine liposome containing iohexol and lomustine solution in rats were simulated using the final PPK model: t (1/2), AUC(0-∞), C (max) were 0.28 ± 0.12, 0.19 ± 0.08, and 0.30 ± 0.13 h; 2.37 ± 0.76, 1.32 ± 0.42, and 0.90 ± 0.29 mg h/L; 5.15 ± 2.22, 3.91 ± 1.90, and 1.87 ± 0.35 μg/mL for heated, non-heated, and control group, respectively. The result indicated that thermosensitive liposome-encapsulated lomustine containing iohexol for CT imaging had different pharmacokinetic characteristics than lomustine solution. Compared with non-heated group, the bioavailability of lomustine was obviously increased in C6 glioma rat plasma.
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
authors.forename: Luning
authors.initials: L
authors.lastname: Zhuang
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Bingjie
authors.initials: B
authors.lastname: Zhang
authors.forename: Mu
authors.initials: M
authors.lastname: Li
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000000981:diagnostic imaging*; D002138:Calibration; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003287:Contrast Media / Q000008:administration & dosage*; D004337:Drug Carriers; D004339:Drug Compounding; D005910:Glioma / Q000000981:diagnostic imaging*; D007275:Injections, Intravenous; D007472:Iohexol / Q000008:administration & dosage*; D008081:Liposomes; D008130:Lomustine / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics*; D015233:Models, Statistical; D011786:Quality Control; D051381:Rats; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D004337:Drug Carriers; D008081:Liposomes; D007472:Iohexol; D008130:Lomustine